KR20020041521A - Novel indole hydrazone derivatives - Google Patents

Novel indole hydrazone derivatives Download PDF

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KR20020041521A
KR20020041521A KR1020000071160A KR20000071160A KR20020041521A KR 20020041521 A KR20020041521 A KR 20020041521A KR 1020000071160 A KR1020000071160 A KR 1020000071160A KR 20000071160 A KR20000071160 A KR 20000071160A KR 20020041521 A KR20020041521 A KR 20020041521A
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compound
formula
methyl
pharmaceutically acceptable
hydrogen
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KR1020000071160A
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Korean (ko)
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이정근
서병철
장명식
송석범
김종훈
이재목
임지웅
윤여홍
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손 경 식
제일제당주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Abstract

PURPOSE: An indole hydrazone derivative and its pharmaceutical acceptable salts are provided. Therefore, the compound can inhibit phosphodiesterase IV or tumor necrosis factor(TNF), so that diseases associated with phosphodiesterase IV or tumor necrosis factor(TNF) can be effectively treated. CONSTITUTION: The indole hydrazone derivative represented by formula(1) and its pharmaceutical acceptable salts are provided, wherein R1 is hydrogen, (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl or benzyl; R2 is selected from i) C(=O)H, ii) C(=X)NH=R4, iii) C(=O)OR5 or iv) pyridine; X is O, S or N-R6; R3 is hydrogen, (C1-C7)alkyl or aryl; R4 is hydrogen or amine; R5 is hydrogen or (C1-C3)alkyl; and R6 is hydrogen or nitrile.

Description

신규한 인돌 히드라존 유도체{NOVEL INDOLE HYDRAZONE DERIVATIVES}Novel indole hydrazone derivatives {NOVEL INDOLE HYDRAZONE DERIVATIVES}

본 발명은 신규한 인돌 히드라존 유도체 또는 그 약학적 허용 염에 관한 것으로, 더 상세하게는 포스포디에스터라제 IV 또는 종양괴사인자(Tumor necrosis factor; TNF)에 억제작용을 갖는 신규한 인돌 히드라존 유도체 또는 그 약학적 허용 염에 관한 것이다. 본 발명의 인돌 히드라존 유도체 또는 그 약학적 허용 염은 천식, 관절염, 골관절염, 기관지염, 만성 기도 폐쇄 질병, 건선, 알레르기성 비염, 피부염, AIDS, HIV, 크론씨(Crohn's) 질병, 패혈증, 패혈병에 의한 충격(shock), 악태증, 기타 염증 질병들 또는 종양괴사인자(TNF)의 생산을 포함하는 질병들에 대한 치료에 유용하다.The present invention relates to a novel indole hydrazone derivative or a pharmaceutically acceptable salt thereof, and more particularly to a novel indole hydrazone having an inhibitory effect on phosphodiesterase IV or tumor necrosis factor (TNF). A derivative or a pharmaceutically acceptable salt thereof. Indole hydrazone derivatives or pharmaceutically acceptable salts thereof of the present invention are used for asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, sepsis It is useful for the treatment of diseases including shock, malnutrition, other inflammatory diseases or the production of tumor necrosis factor (TNF).

포스포디에스터라제는 화학 전달 물질의 하나로서 싸이클릭 뉴클레오타이드를 가수분해하는 효소이다. 특히 포스포디에스터라제 IV는 선택적으로 싸이클릭 아데노신 3',5'-모노포스페이트를 불활성의 아데노신 3',5'-모노포스페이트로 가수 분해하는 효소이며 싸이클릭 아데노신 3',5'-모노포스페이트는 외부 세포 자극에 대한 세포의 반응을 조절 담당하는 이차전달자(second messenger)로서 기관지 근육의 이완 작용을 한다.Phosphodiesterases are enzymes that hydrolyze cyclic nucleotides as one of the chemical delivery agents. In particular phosphodiesterase IV is an enzyme that selectively hydrolyzes cyclic adenosine 3 ', 5'-monophosphate to inactive adenosine 3', 5'-monophosphate and is a cyclic adenosine 3 ', 5'-monophosphate Is a second messenger responsible for regulating the response of cells to external cell stimuli.

포스포디에스터라제 IV의 억제작용은 싸이클릭 아데노신 3',5'-모노포스페이트의 농도를 유지함으로써 기관지 경련을 방지할 수 있으며 덧붙여서 항염증 작용을 한다. 따라서 포스포디에스터라제 IV를 억제하는 화합물들은 천식, 염증성 질환 등의 치료제로서 유용하다.Inhibitory action of phosphodiesterase IV prevents bronchial spasms by maintaining the concentration of cyclic adenosine 3 ', 5'-monophosphate and in addition has anti-inflammatory action. Thus compounds that inhibit phosphodiesterase IV are useful as therapeutic agents for asthma, inflammatory diseases and the like.

종양괴사인자(TNF)는 악태증을 포함한 많은 감염 질환 그리고 자가 면역질환과 관련이 있다고 알려졌으며, 또한 TNF은 패혈증와 패혈병에 의한 충격(shock)에서 보여지는 염증 반응의 주요 매개체인 것으로 나타났다.Tumor necrosis factor (TNF) is known to be associated with many infectious diseases including automatism and autoimmune diseases, and TNF has also been shown to be a major mediator of the inflammatory response seen in sepsis and septic shock.

포스포디에스터라제 Ⅳ 억제제들은 일반적으로 종양괴사인자인 TNF-α 에 대해서도 저해작용을 하는 것으로 알려져 있고 이는 임상학적으로 밝혀진 것이다(참고: Christian Schudt, Phosphodiesterase Inhibitors).Phosphodiesterase IV inhibitors are generally known to inhibit TNF-α, a tumor necrosis factor, and have been clinically identified (Christian Schudt, Phosphodiesterase Inhibitors).

포스포디에스터라제 IV 또는 종양괴사인자(TNF)에 대한 억제제로서 작용하는 몇몇 화합물들이 알려진 바 있다.Several compounds have been known to act as inhibitors of phosphodiesterase IV or tumor necrosis factor (TNF).

예를 들면 인돌 모핵을 가진 구조를 지닌 물질이 보고된 바 있다.For example, substances with structures with indole nuclei have been reported.

롱프랑로라(Rhone Poulenc Rorer)회사는 문헌[Bioorg. Med. Chem. Lett.1998, 8, 3053-3058] 에서 인돌모핵을 이용하여 카테콜 에테르의 모핵인 3-메톡시-4-사이클로펜톡시의 기본적인 구조에서 롱프랑로라 회사가 개발한 RP-73401의 측쇄(side chain)인 4-아미노-3,5-다이클로로피리딘을 도입한 새로운 인돌화합물에관한 문헌을 보고하였다.The Rhone Poulenc Rorer company is known from Bioorg. Med. Chem. Lett . 1998 , 8, 3053-3058] Side chain of RP-73401 developed by LongFranola Company in the basic structure of 3-methoxy-4-cyclopentoxy, the mother core of catechol ether using indole nucleus The literature on new indole compounds with phosphorus 4-amino-3,5-dichloropyridine has been reported.

(A)(A)

상기 식에서,Where

R1는 (C1∼C5)저급알킬기, 아릴 또는 벤질기이고,R 1 is a (C 1 -C 5 ) lower alkyl group, an aryl or benzyl group,

R2는 (C5∼C9)싸이클로화합물, 치환된 아릴 또는 p-톨루엔술폰기이다.R 2 is a (C 5 -C 9 ) cyclo compound, substituted aryl or p-toluenesulphone group.

화이자 회사는 WO 제98/50367호에서 카테콜 에테르의 모핵인 3-메톡시-4-사이클로펜톡시의 기본적인 구조에서 스미스 클라인 비참(Smith Kline Beecham) 회사가 개발한 SB-207499의 측쇄인 시아노싸이클로헥실카르복실산을 인다졸 유도체에 도입한 화합물에 대한 특허를 발표하였다.Pfizer Company, in WO 98/50367, describes cyano, the side chain of SB-207499, developed by Smith Kline Beecham, in the basic structure of 3-methoxy-4-cyclopentoxy, the parent of catechol ethers. A patent is disclosed for a compound which introduces cyclohexylcarboxylic acid into an indazole derivative.

(B)(B)

상기 식에서,Where

R1는 (C1∼C10)알킬 또는 -(CH2)n(페닐)이고 여기서 n은 0 ∼ 2 이며,R 1 is (C 1 -C 10 ) alkyl or-(CH 2 ) n (phenyl), where n is 0-2,

R2는 (C1∼C10)알킬, 알케닐 또는 페닐이고,R 2 is (C 1 -C 10 ) alkyl, alkenyl or phenyl,

R3및 R4는 -C(O)OR5이며,R 3 and R 4 are -C (O) OR 5 ,

R5는 H 또는 (C1∼C6)알킬기이다R 5 is H or a (C 1 -C 6 ) alkyl group

위와 같은 화합물들이 보고된 바 있으나, 구조적으로 본 발명의 화합물과 상이함을 알 수 있다.Although the above compounds have been reported, it can be seen that they are structurally different from the compounds of the present invention.

본 발명자들은 오랜 기간에 걸쳐 연구한 결과, 포스포디에스터라제 Ⅳ 또는 TNF에 대해 억제작용을 가지는 신규한 인돌 히드라존 유도체 또는 그 약학적 허용 염을 제조하게 되어 본 발명을 완성하였다. 즉, 본 발명은 하기 화학식 1로 표시되는 인돌 히드라존 유도체, 이의 이성질체, 이의 이성질체들의 혼합물 및 이들의 약학적 허용 염을 제공하는 데 목적이 있다.The present inventors have conducted a long study to prepare a novel indole hydrazone derivative or a pharmaceutically acceptable salt thereof having an inhibitory effect on phosphodiesterase IV or TNF. That is, an object of the present invention is to provide an indole hydrazone derivative represented by Formula 1 below, an isomer thereof, a mixture of isomers thereof, and a pharmaceutically acceptable salt thereof.

본 발명은 신규한 인돌 히드라존 유도체 또는 그 약학적 허용 염에 관한 것이다. 이들은 포스포디에스터라제 Ⅳ 또는 종양괴사인자(TNF)에 대해 억제 작용을 가지며, 천식, 관절염, 골관절염, 기관지염, 만성 기도 폐쇄 질병, 건선, 알레르기성 비염, 피부염, AIDS, HIV, 크론씨(Crohn's) 질병, 패혈증, 패혈병에 의한 충격(shock), 악태증과 같은 기타 염증 질병들 또는 종양괴사인자(TNF)의 생산을 포함하는 질병들에 대한 치료에 유용하다.The present invention relates to novel indole hydrazone derivatives or pharmaceutically acceptable salts thereof. They have an inhibitory effect on phosphodiesterase IV or tumor necrosis factor (TNF) and are asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's It is useful for the treatment of diseases, sepsis, septic shock, other inflammatory diseases such as atherosclerosis or diseases including the production of tumor necrosis factor (TNF).

구체적으로, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 또는 기하 이성질체, 이의 광학 또는 기하 이성질체들의 혼합물, 이들의 약학적 허용 염 및 이들의 제조방법에 관한 것이다.Specifically, the present invention relates to a compound represented by the following formula (1), optical or geometric isomers thereof, mixtures of optical or geometric isomers thereof, pharmaceutically acceptable salts thereof, and methods for preparing the same.

상기 식에서,Where

R1는 수소, (C1-C7)알킬, (C3-C7)사이클로알킬, 페닐 또는 벤질이고,R 1 is hydrogen, (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or benzyl,

R2는 선택적으로R 2 is optionally

i) -C(=O)H,i) -C (= O) H,

ii) -C(=X)NH-R4,ii) -C (= X) NH-R 4 ,

ⅲ) -C(=O)OR5, 또는Iii) -C (= O) OR 5 , or

ⅳ) 피리딘기이며,Iii) a pyridine group,

X는 O, S 또는 N-R6이고,X is O, S or NR 6 ,

R3는 수소, (C1-C7)알킬 또는 아릴기이며,R 3 is hydrogen, (C 1 -C 7 ) alkyl or an aryl group,

R4는 수소 또는 아민기이고,R 4 is hydrogen or an amine group,

R5는 수소 또는 (C1-C3)알킬이며,R 5 is hydrogen or (C 1 -C 3 ) alkyl,

R6는 수소 또는 니트릴기이다.R 6 is hydrogen or a nitrile group.

상기 화학식 1에서, 알킬기는 직쇄형(unbranched) 및 측쇄형(branched)을 포함한다.In Formula 1, the alkyl group includes straight chain and branched chain.

또한, 상기 화학식 1 에 있어서,In addition, in Chemical Formula 1,

R1는 싸이클로펜틸 또는 벤질이고,R 1 is cyclopentyl or benzyl,

R2는 선택적으로R 2 is optionally

i) -C(=O)H,i) -C (= O) H,

ii) -C(=X)NH-R4,ii) -C (= X) NH-R 4 ,

ⅲ) -C(=O)OR5, 또는Iii) -C (= O) OR 5 , or

ⅳ) 피리딘기이며,Iii) a pyridine group,

X는 O, S 또는 N-R6이고,X is O, S or NR 6 ,

R3는 수소 또는 메틸기이며,R 3 is hydrogen or a methyl group,

R4는 수소 또는 아민기이고,R 4 is hydrogen or an amine group,

R5는 수소 또는 에틸기이며,R 5 is hydrogen or an ethyl group,

R6는 수소인 화합물이 바람직하다.It is preferable that R 6 is hydrogen.

본 발명의 범주에 포함되는 더 바람직한 화학식 1의 화합물들은 다음과 같다:More preferred compounds of formula 1 that fall within the scope of the present invention are as follows:

(E)-2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복스아미드,(E) -2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxamide,

(E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)히드라진카르복스아미드,(E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) hydrazinecarboxamide,

에틸 2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복실레이트,Ethyl 2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxylate,

2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복실산,2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxylic acid,

2N-(3-메틸-1H-6-인돌)카바알데하이드 2-피리디노히드라존,2N- (3-methyl- 1H -6-indole) carbaaldehyde 2-pyridinohydrazone,

(E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)히드라진카르보티오아미드,(E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) hydrazinecarbothioamide,

(E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴에틸렌)히드라진카르복사아미드,(E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylethylene) hydrazinecarboxamide,

(E)-2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복스이미다미드,(E) -2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboximidamide,

(E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)카르보히드라자이드,(E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) carbohydrazide,

(E)-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)-2N-아세틱히드라존,(E)-(3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) -2N-acetichydrazone,

(E)-2N-(3-메틸-1N-벤질-1H-6-인돌릴메틸렌)히드라진카르복사아미드.(E) -2N- (3-methyl-1N-benzyl- 1H -6-indolylmethylene) hydrazinecarboxamide.

본 발명의 화학식 1의 화합물의 약학적 허용 염은 예를들면 염산염, 황산염 등을 포함하나, 이에 한정되는 것은 아니다.Pharmaceutically acceptable salts of the compounds of formula 1 of the present invention include, but are not limited to, for example, hydrochloride, sulfate, and the like.

또, 본 발명의 화학식 1의 화합물 또는 그 약학적 허용 염은 하나 이상의 광학이성질체 형태로 존재할 수 있으며, 본 발명은 단일의 광학이성질체 형태 또는 광학이성질체들의 혼합물 형태의 화학식 1의 화합물 또는 그 약학적 허용 염을 포함한다. 즉, 본 발명은 화학식 1의 화합물, 이의 광학이성질체, 이의 광학이성질체들의 혼합물, 또는 이들의 약학적 허용 염을 포함한다.In addition, the compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention may exist in one or more optical isomer forms, and the present invention provides a compound of formula 1 or a pharmaceutically acceptable form thereof in the form of a single optical isomer or a mixture of optical isomers. Salts. That is, the present invention includes a compound of Formula 1, an optical isomer thereof, a mixture of optical isomers thereof, or a pharmaceutically acceptable salt thereof.

또한, 본 발명의 화학식 1의 화합물 또는 그 약학적 허용 염은 하나 이상의 기하이성질체 형태로 존재할 수 있으며, 본 발명은 단일의 기하이성질체 형태 또는 기하이성질체들의 혼합물 형태의 화학식 1의 화합물 또는 그 약학적 허용 염을 포함한다. 즉, 본 발명은 화학식 1의 화합물, 이의 기하이성질체, 이의 기하이성질체들의 혼합물, 또는 이들의 약학적 허용 염을 포함한다.In addition, the compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention may exist in one or more geometric isomeric forms, and the present invention provides a compound of formula 1 or a pharmaceutically acceptable form thereof in the form of a single geometric isomer or a mixture of geometric isomers. Salts. That is, the present invention includes a compound of formula 1, a geometric isomer thereof, a mixture of geometric isomers thereof, or a pharmaceutically acceptable salt thereof.

상기 화학식 1의 화합물은 이중결합을 보유하기 때문에 본 발명은 시스(cis) 및 트랜스(trans) 이성질체를 포함한다. 즉, 본 발명의 화합물은 기하구조 이성질체 혼합물 뿐만 아니라 각각의 기하구조 이성질체를 포함한다. 기하구조 이성질체는 우선 순위 명명법에 의거하여 E, Z으로 명명한다.Since the compound of Formula 1 has a double bond, the present invention includes cis and trans isomers. That is, the compounds of the present invention include each geometric isomer as well as a geometric isomeric mixture. Geometric isomers are named E and Z based on priority nomenclature.

E/Z 이성질체는 하기 실시예에 기재된 통상적인 방법에 의해 합성할 수 있으며, 실시예에서 나타낸 방법으로 기하구조 이성질체 E, Z를 순수하게 분리할 수 있다.E / Z isomers can be synthesized by the conventional methods described in the Examples below, and the geometrical isomers E and Z can be separated purely by the methods shown in the Examples.

본 발명에서는 E-형태의 화합물이 바람직하다.In the present invention, compounds of the E-form are preferred.

또한 본 발명은 약학적으로 허용가능한 담체와 함께 유효량의 상기 화학식 1의 화합물, 이의 이성질체, 이의 이성질체들의 혼합물 및 이들의 약학적 허용 염으로 구성된 군 중에서 선택된 화합물을 포함하는, 포스포디에스터라제 IV 또는 종양괴사인자를 저해하기 위한 약학 조성물에 관한 것이다. 또한, 본 발명은 약학적으로 허용가능한 담체와 함께 유효량의 상기 화학식 1의 화합물, 이의 이성질체, 이의 이성질체들의 혼합물 및 이들의 약학적 허용 염으로 구성된 군 중에서 선택된 화합물을 포함하는, 천식, 관절염, 골관절염, 기관지염, 만성 기도 폐쇄 질병, 건선, 알레르기성 비염, 피부염, AIDS, HIV, 크론씨(Crohn's) 질병, 패혈증, 패혈병에 의한 충격(shock), 악태증, 기타 염증 질병들 또는 종양괴사인자의 생산을 포함하는 질병들의 치료에 유용한 약학 조성물에 관한 것이다.The present invention also provides a phosphodiesterase IV comprising a compound selected from the group consisting of an effective amount of a compound of Formula 1, an isomer thereof, a mixture of isomers thereof and a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Or to a pharmaceutical composition for inhibiting tumor necrosis factor. In addition, the present invention comprises an effective amount of a compound selected from the group consisting of a compound of Formula 1, an isomer thereof, a mixture of isomers thereof and a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, asthma, arthritis, osteoarthritis , Bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock, etiology, other inflammatory diseases or production of tumor necrosis factor It relates to a pharmaceutical composition useful for the treatment of diseases comprising.

하기 반응식은 본 발명의 화학식 1로 표시되는 신규 화합물들의 제조방법을 예시한 것이며, 본 발명의 화합물의 제조방법이 하기 반응식으로 제한되는 것은 아니다. 하기 제조방법의 여러 변형 방법들이 당업자에게 자명할 것이다. 달리 언급되지 않은 한, 하기에서 R1, R2및 R3은 화학식 1에 대해 상기에 정의한 바와 동일하다.The following reaction schemes exemplify the preparation method of the novel compounds represented by the general formula (1) of the present invention, and the preparation method of the compounds of the present invention is not limited to the following reaction schemes. Various modifications of the following preparation methods will be apparent to those skilled in the art. Unless stated otherwise, in the following R 1 , R 2 and R 3 are the same as defined above for Formula (1).

반응식Scheme

상기 반응식을 구체적으로 설명하면 다음과 같다.A detailed description of the reaction scheme is as follows.

우선, 메틸 3-포밀인돌-6-카르복실레이트를 무수 테트라하이드로퓨란 용매중에서 리튬알루미늄하이드라이드를 사용하여 환원반응을 진행시킨 후 형성된 하이드록시인돌 유도체를 이산화망간 또는 피리디니움다이크롬에트를 사용하여 하기 알데히드를 합성한 후 R1-Br 을 도입하여 하기 알데히드를 합성한다.First, the methyl 3-formylindole-6-carboxylate is subjected to a reduction reaction using lithium aluminum hydride in anhydrous tetrahydrofuran solvent, and then the hydroxyindole derivative formed is prepared using manganese dioxide or pyridinium dichromate. The following aldehydes are synthesized after R 1 -Br is synthesized.

하기 알데히드 화합물에 R3-리튬 유도체 또는 그리나르(Grignard) 시약을 사용하여 반응을 진행시켜 알콜 유도체를 합성한 다음 피리디니움다이크롬에트 또는 이산화망간을 이용하여 하기 케톤유도체 화합물을 합성한다.The following aldehyde compound is subjected to a reaction using an R 3 -lithium derivative or a Grignard reagent to synthesize an alcohol derivative, and then a pythonium dichromate or manganese dioxide is used to synthesize the following ketone derivative compound.

하기 알데히드 화합물을 다양한 히드라진 화합물과 알콜용매중에서 농염산, 농황산 등 산촉매를 사용하여 반응시켜 화학식 1의 화합물을 합성하였다.The following aldehyde compounds were reacted with various hydrazine compounds and alcohol solvents using acid catalysts such as concentrated hydrochloric acid and concentrated sulfuric acid to synthesize the compound of Formula 1.

화학식 1Formula 1

하기 케톤 유도체와 히드라진의 축합반응은 상기의 알데히드 반응과 유사하게 반응을 진행시키되 반응시간 및 산촉매의 양을 조절하면서 반응을 진행시켜 화학식 1의 화합물을 합성하는 방법을 하기 반응식 4에 나타내었다.The condensation reaction of the ketone derivative and the hydrazine is performed in a manner similar to the above aldehyde reaction, but the reaction proceeds while controlling the reaction time and the amount of the acid catalyst.

화학식 1Formula 1

본 명세서내 각 반응에서, 생성물은 당업계에 공지된 통상의 방법에 의하여 반응계로부터 분리 및/또는 정제될 수 있다. 분리 및 정제방법의 예로는, 증류(대기압하 증류 및 감압증류를 포함), 재결정, 칼럼 크로마토그래피, 이온교환 크로마토그래피, 겔 크로마토그래피, 친화성 크로마토그래피, 박층 크로마토그래피, 상 분리, 용매 추출, 세척 등을 이용할 수 있다. 정제는 각 반응후마다, 또는 일련의 반응 후에 수행할 수 있다.In each reaction herein, the product can be separated and / or purified from the reaction system by conventional methods known in the art. Examples of separation and purification methods include distillation (including distillation under atmospheric pressure and distillation under reduced pressure), recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, thin layer chromatography, phase separation, solvent extraction, Washing and the like can be used. Purification can be carried out after each reaction or after a series of reactions.

본 발명의 화합물의 합성을 위해 필요한 출발물질 및 시약은 문헌의 방법에 의해 또는 전술한 방법 및 하기 실시예에 예시된 방법에 의해 용이하게 제조가능하거나, 상업적으로 구입가능하다.Starting materials and reagents necessary for the synthesis of the compounds of the present invention are readily prepared or commercially available by the methods of the literature or by the methods exemplified above and in the Examples below.

하기에서 실시예를 들어 본 발명을 더 상세히 설명하겠지만, 하기 실시예는 예시의 목적으로만 제공된 것이며, 본 발명의 범주 및 범위가 하기 실시예에 의해 제한되는 것은 아니다.Although the present invention will be described in more detail with reference to the following examples, the following examples are provided for illustrative purposes only, and the scope and scope of the present invention are not limited by the following examples.

참고예 1. 3-메틸-1H-6-인돌릴메탄올Reference Example 1. 3-Methyl- 1H -6-indolylmethanol

메틸 3-포밀인돌-6-카르복실레이트(1.0 g, 4.92 mmol)를 무수 테트라하이드로퓨란(40 ml)중에서 실온에서 15분간 현탁시킨 후 리튬알루미늄하이드라이드(0.79 g, 16.9 mmole) 분말을 천천히 투입했다. 현탁액을 25 ℃에서 20분간 교반한 다음 서서히 가온하여 2시간 동안 환류시켰다. 반응용액을 실온으로 온도를 낮춘 후 2시간동안 추가로 교반하고 다시 0 ℃로 냉각시켰다. 1.0N 염산용액(150 ml)에 냉각시킨 반응용액을 천천히 적가하고 에틸아세테이트(150 ml X 2)로 추출했다. 분리한 유기층을 염수(brine) 용액 및 증류수로 연속하여 세척하고 무수 황산 마그네슘으로 건조, 여과했다. 분리된 용액을 감압증류하여 연갈색의 고상 표제화합물(1.20 g)을 수득하였다.Methyl 3-formylindole-6-carboxylate (1.0 g, 4.92 mmol) was suspended in anhydrous tetrahydrofuran (40 ml) for 15 minutes at room temperature, followed by slowly adding lithium aluminum hydride (0.79 g, 16.9 mmole) powder. did. The suspension was stirred at 25 ° C. for 20 minutes and then slowly warmed to reflux for 2 hours. The reaction solution was cooled to room temperature and further stirred for 2 hours, and then cooled to 0 ° C. The reaction solution cooled to 1.0 N hydrochloric acid solution (150 ml) was slowly added dropwise and extracted with ethyl acetate (150 ml X 2). The separated organic layer was washed successively with brine solution and distilled water, dried over anhydrous magnesium sulfate and filtered. The separated solution was distilled under reduced pressure to give a light brown solid title compound (1.20 g).

1H NMR(CDCl3, ) : 2.34(3H, d J=1.0Hz) 4.78(2H, s) 6.97(1H, d) 1 H NMR (CDCl 3 ,): 2.34 (3H, d J = 1.0 Hz) 4.78 (2H, s) 6.97 (1H, d)

7.11(1H, d) 7.34(1H, s) 7.55(1H, d J=9.1Hz)7.11 (1H, d) 7.34 (1H, s) 7.55 (1H, d J = 9.1 Hz)

7.92(1H, brs)7.92 (1 H, brs)

참고예 2. 3-메틸-1H-6-인돌카바알데하이드Reference Example 2. 3-Methyl- 1H -6-indolecarbaaldehyde

참고예 1에서 합성한 6-하이드록시메틸-3-메틸인돌(1.2 g, 7.44 mmole)을 무수 다이클로로메탄에 용해시킨 후 실온에서 10시간 교반하면서 이산화망간 85%(3.80 g, 37.2 mmole)을 3시간마다 투입했다. 반응용액을 여과하고 감압증류하여 연갈색의 고상 표제 화합물(1.03 g)을 수득하였다.6-hydroxymethyl-3-methylindole (1.2 g, 7.44 mmole) synthesized in Reference Example 1 was dissolved in anhydrous dichloromethane, and stirred for 10 hours at room temperature to yield 85% (3.80 g, 37.2 mmole) of manganese dioxide. Injected every hour. The reaction solution was filtered and distilled under reduced pressure to give a light brown solid title compound (1.03 g).

1H NMR(CDCl3): 2.35(3H, d J=1.0Hz) 7.21(1H, dd, J=1.0, 1.1Hz) 1 H NMR (CDCl 3 ): 2.35 (3H, d J = 1.0 Hz) 7.21 (1H, dd, J = 1.0, 1.1 Hz)

7.66(2H, d J=1.1Hz) 7.89(1H, d J=1.0Hz) 8.58(1H, brs)7.66 (2H, d J = 1.1 Hz) 7.89 (1H, d J = 1.0 Hz) 8.58 (1 H, brs)

10.06(1H, s)10.06 (1H, s)

참고예 3. 3-메틸-1N-싸이클로펜틸-1H-6-인돌카바알데하이드Reference Example 3. 3-Methyl-1N-cyclopentyl- 1H -6-indolecarbaaldehyde

참고예 2에서 합성한 3-메틸-1H-6-인돌카바알데하이드 0.8 g(5.0 mmole)을 무수 N,N-다이메틸포름아마이드 20 ml에 용해시킨 후 아르곤 가스로 충진하고 싸이클로펜틸브로마이드 5.4 ml(50.2 mmole)을 투입하고 실온에서 10분간 교반시켰다. 반응용액을 0℃로 냉각시키고 수소화나트륨(sodium hydride) 0.44 g(60%)을 2시간 동안 서서히 투입한 후 실온으로 반응온도를 유지하고 4시간 교반했다. 에틸아세테이트 50 ml로 반응용액을 희석하고 1.0N 수산화나트륨 50 ml로 3회 세척한 다음 분리한 용액을 무수 황산 마그네슘으로 건조시켰다. 여과한 용액을 감압증류하여 연갈색의 고상 표제 화합물(0.88 g)을 수득하였다.0.8 g (5.0 mmole) of 3-methyl- 1H -6-indolecarbaaldehyde synthesized in Reference Example 2 was dissolved in 20 ml of anhydrous N, N-dimethylformamide, filled with argon gas, and 5.4 ml of cyclopentylbromide ( 50.2 mmole) was added and stirred at room temperature for 10 minutes. The reaction solution was cooled to 0 ° C. and 0.44 g (60%) of sodium hydride was slowly added thereto for 2 hours, and then the reaction temperature was maintained at room temperature and stirred for 4 hours. The reaction solution was diluted with 50 ml of ethyl acetate, washed three times with 50 ml of 1.0 N sodium hydroxide, and the separated solution was dried over anhydrous magnesium sulfate. The filtered solution was distilled under reduced pressure to give a light brown solid title compound (0.88 g).

1H NMR(CDCl3): 1.64(2H, m) 1.91(4H, m) 2.01(2H, m) 2.35(3H, d, 1 H NMR (CDCl 3 ): 1.64 (2H, m) 1.91 (4H, m) 2.01 (2H, m) 2.35 (3H, d,

J=1.0Hz) 7.23(1H, dd, J=1.0, 1.1Hz) 7.66(2H, d J=1.1Hz)J = 1.0 Hz) 7.23 (1H, dd, J = 1.0, 1.1 Hz) 7.66 (2H, d J = 1.1 Hz)

7.89(1H, d J=1.0Hz) 8.60(1H, brs) 10.05(1H, s)7.89 (1H, d J = 1.0 Hz) 8.60 (1H, brs) 10.05 (1H, s)

참고예 4. 1-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴)-1-에탄올Reference Example 4. 1- (3-Methyl-1N-cyclopentyl- 1H -6-indolyl) -1-ethanol

참고예 3의 3-메틸-1N-싸이클로펜틸-1H-6-인돌카바알데하이드 1.0 g(6.23 mmole)를 무수 테트라하이드로퓨란(50 ml)에 용해시킨 후 아르곤 가스로 충진하고 -40 ℃이하로 냉각시켰다. 메틸리튬 9.0 ml(1.4M, 에테르)용액을 -40℃ 이하로 온도를 유지하면서 서서히 30분에 걸쳐 적가한 후 상기 온도에서 1시간 동안 교반한 다음 실온으로 서서히 가온하여 30분간 교반했다. -40℃에서 포화 염화암모늄 용액(100 ml)을 반응용액에 서서히 적가한 후 20분간 교반한 다음 에틸아세테이트(100 ml X 2회)를 넣어 유기용액층을 추출 분리했다. 분리된 유기층을 무수 황산 마그네슘으로 건조시킨 후 여과하고 농축하여 연노란색의고상물(0.92 g)을 수득하였다.1.0 g (6.23 mmole) of 3-methyl-1N-cyclopentyl- 1H -6-indolecarbaaldehyde of Reference Example 3 was dissolved in anhydrous tetrahydrofuran (50 ml), and then charged with argon gas and cooled to -40 ° C or lower. I was. A 9.0 ml solution of methyl lithium (1.4 M, ether) was slowly added dropwise over 30 minutes while maintaining the temperature at -40 ° C. or lower, and then stirred at the temperature for 1 hour, and then slowly warmed to room temperature and stirred for 30 minutes. Saturated ammonium chloride solution (100 ml) was slowly added dropwise to the reaction solution at -40 ° C, stirred for 20 minutes, and ethyl acetate (100 ml X 2 times) was added thereto to extract and separate the organic solution layer. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a pale yellow solid (0.92 g).

1H NMR(CDCl3): 1.62(2H, m) 1.93(4H, m) 2.03(2H, m) 2.38(3H, d, 1 H NMR (CDCl 3 ): 1.62 (2H, m) 1.93 (4H, m) 2.03 (2H, m) 2.38 (3H, d,

J=1.0Hz) 2.56(3H, d) 4.57(1H, q) 7.25(1H, dd, J=1.0,J = 1.0 Hz) 2.56 (3H, d) 4.57 (1H, q) 7.25 (1H, dd, J = 1.0,

1.1Hz) 7.61(2H, d J=1.1Hz) 7.80(1H, d J=1.0Hz)1.1 Hz) 7.61 (2H, d J = 1.1 Hz) 7.80 (1H, d J = 1.0 Hz)

8.60(1H, brs)8.60 (1H, brs)

참고예 5. 1-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴)-1-에탄온Reference Example 5. 1- (3-Methyl-1N-cyclopentyl- 1H -6-indolyl) -1-ethanone

참고예 4에서 얻은 유상물 0.90 g을 다이클로로메탄(100 ml)에 용해한 후 피리디늄 다이크롬메이트 50.0 g을 투입한 다음 실온에서 24시간 동안 교반 후 에테르(200 ml)를 첨가하여 1시간 동안 교반시킨 후, 여과하고 에테르(100 ml), 에틸아세테이트(100 ml)로 세척하였다. 수득된 반응액을 농축하고 디클로로메탄의 실리카겔(150 g)에 충진하여 여분의 불순물을 제거하였다. 수득된 유기층을 농축하여 연노란색의 표제 고상물 0.75 g을 수득하였다.0.90 g of the oil obtained in Reference Example 4 was dissolved in dichloromethane (100 ml), 50.0 g of pyridinium dichromate was added thereto, followed by stirring at room temperature for 24 hours, followed by addition of ether (200 ml) for 1 hour. After filtration, the mixture was washed with ether (100 ml) and ethyl acetate (100 ml). The obtained reaction solution was concentrated and filled with silica gel (150 g) of dichloromethane to remove excess impurities. The obtained organic layer was concentrated to give 0.75 g of a pale yellow title solid.

1H NMR(CDCl3): 1.66(2H, m) 1.94(4H, m) 2.02(2H, m) 2.32(3H, d, 1 H NMR (CDCl 3 ): 1.66 (2H, m) 1.94 (4H, m) 2.02 (2H, m) 2.32 (3H, d,

J=1.0Hz) 2.52(3H, s) 7.18(1H, dd, J=1.0, 1.1Hz)J = 1.0 Hz) 2.52 (3H, s) 7.18 (1H, dd, J = 1.0, 1.1 Hz)

7.60(2H, d J=1.1Hz) 7.81(1H, d J=1.0Hz) 8.59(1H, brs)7.60 (2H, d J = 1.1 Hz) 7.81 (1H, d J = 1.0 Hz) 8.59 (1 H, brs)

참고예 6. 3-메틸-1N-벤질-1H-6-인돌카바알데하이드Reference Example 6. 3-Methyl-1N-benzyl- 1H -6-indolecarbaaldehyde

참고예 2에서 합성한 3-메틸-1H-6-인돌카바알데하이드 0.2 g(1.2 mmole)을 무수 N,N-다이메틸포름아마이드 4 ml에 용해시킨 후 아르곤 가스로 충진하고 벤질브로마이드 0.76 ml(6.3 mmole)을 투입하고 실온에서 10분간 교반했다. 반응용액을 0℃로 냉각시키고 수소화나트륨 0.14 g(60%)을 2시간 동안 서서히 투입한 후 실온으로 반응온도를 유지하고 4시간 교반했다. 에틸아세테이트 50 ml로 반응용액을 희석하고 1.0N 수산화나트륨 50 ml로 3회 세척한 다음 분리한 용액을 무수 황산 마그네슘으로 건조시켰다. 여과한 용액을 감압증류하여 연갈색의 고상 표제 화합물(0.21 g)을 수득하였다.0.2 g (1.2 mmole) of 3-methyl- 1H -6-indolecarbaaldehyde synthesized in Reference Example 2 was dissolved in 4 ml of anhydrous N, N-dimethylformamide, filled with argon gas, and 0.76 ml (6.3 ml of benzylbromide). mmole) was added and stirred at room temperature for 10 minutes. The reaction solution was cooled to 0 ° C., and 0.14 g (60%) of sodium hydride was slowly added for 2 hours, and the reaction temperature was maintained at room temperature, followed by stirring for 4 hours. The reaction solution was diluted with 50 ml of ethyl acetate, washed three times with 50 ml of 1.0 N sodium hydroxide, and the separated solution was dried over anhydrous magnesium sulfate. The filtered solution was distilled under reduced pressure to give a light brown solid title compound (0.21 g).

1H NMR(CDCl3) : 2.32 (3H, s) 5.27 (2H,s) 6.98 (1H, d, J=1.1Hz) 1 H NMR (CDCl 3 ): 2.32 (3H, s) 5.27 (2H, s) 6.98 (1H, d, J = 1.1 Hz)

7.17 (2H, d, J=6.4Hz) 7.32 (3H, m) 7.43 (1H, s)7.17 (2H, d, J = 6.4 Hz) 7.32 (3H, m) 7.43 (1H, s)

7.45 (1H, dd, J=8.3, 1.3 Hz) 7.59 (1H, d. J=8.3 Hz)7.45 (1H, doublet of doublets, J = 8.3, 1.3 Hz) 7.59 (1H, d. J = 8.3 Hz)

7.79 (1H,s) 10.15(1H, s)7.79 (1 H, s) 10.15 (1 H, s)

실시예 1. (E)-2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복스아미드Example 1. (E) -2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxamide

참고예 2의 화합물 3-메틸-1H-6-인돌카바알데하이드 0.070 g(0.44 mmole)을 에탄올 20 ml에 용해한 후 세미카바자이드 0.08 g(20.70 mmole)과 농염산 촉매량을 반응용액에 투입하고 14시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 액상을 디클로로메탄 50 ml에 용해시키고 유기층을 증류수 50 ml(2회)로 세척했다. 분리한 유기층을 감압증류하여 얻은 고상물을 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올 = 95:5 )법을 이용하여 백색의 표제 고상물 0.086 g(90.4%)을 수득하였다.Dissolve 0.070 g (0.44 mmole) of Compound 3-methyl- 1H -6-indolecarbaaldehyde of Reference Example 2 in 20 ml of ethanol, and then add 0.08 g (20.70 mmole) of semicarbazide and concentrated hydrochloric acid to the reaction solution. Reflux for a while. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the liquid phase was dissolved in 50 ml of dichloromethane, and the organic layer was washed with 50 ml (2 times) of distilled water. The separated organic layer was distilled under reduced pressure to give 0.086 g (90.4%) of a white title solid by column chromatography (silica gel, dichloromethane: methanol = 95: 5).

M.P : 250℃ 분해M.P: 250 ℃ decomposition

1H NMR(DMSO-d6) 2.25(3H, s) 6.35(2H, brs) 7.16(1H, dd J=1.0, 1.1Hz) 1 H NMR (DMSO-d 6 ) 2.25 (3H, s) 6.35 (2H, brs) 7.16 (1H, doublet of doublets, 1.0 Hz, 1.1 Hz)

7.46(2H, m) 7.52(1H, s) 7.92(1H, d J=1.0Hz)7.46 (2H, m) 7.52 (1H, s) 7.92 (1H, d J = 1.0 Hz)

10.21(1H, s) 10.88(1H, s)10.21 (1H, s) 10.88 (1H, s)

실시예 2. (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)히드라진카르복스아미드Example 2. (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) hydrazinecarboxamide

참고예 3의 화합물 3-메틸-1N-싸이클로펜틸-1H-6-인돌카바알데하이드 0.30 g(1.3 mmole)을 에탄올 40 ml에 용해시킨 후 세미카바자이드 0.30 g(2.6 mmole)과 농염산 촉매량을 반응용액에 투입하고 14시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 액상을 디클로로메탄 100 ml에 용해시키고 유기층을 증류수 100 ml(2회)로 세척했다. 분리한 유기층을 감압증류하여 얻은 고상물을 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올 = 95:5 )법을 이용하여 백색의 표제 고상물 0.32 g(85.3%)을 수득하였다.0.30 g (1.3 mmole) of 3-methyl-1N-cyclopentyl- 1H -6-indolecarbaaldehyde of Reference Example 3 was dissolved in 40 ml of ethanol, and then 0.30 g (2.6 mmole) of semicarbazide was reacted with a concentrated amount of concentrated hydrochloric acid. It was added to the solution and refluxed for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then dissolved in 100 ml of dichloromethane. The organic layer was washed with 100 ml of distilled water (twice). 0.32 g (85.3%) of white title solids were obtained by column chromatography (silica gel, dichloromethane: methanol = 95: 5).

M.P : 190 ∼ 192 ℃M.P: 190 ~ 192 ℃

1H NMR(CDCl3) 1.72(2H, m) 1.89(4H, m) 2.19(2H, m) 2.31(3H, d, 1 H NMR (CDCl 3 ) 1.72 (2H, m) 1.89 (4H, m) 2.19 (2H, m) 2.31 (3H, d,

J=0.5Hz) 4.75(1H, m) 7.03(1H, s) 7.44(1H, dd J=8.2,J = 0.5 Hz) 4.75 (1H, m) 7.03 (1H, s) 7.44 (1H, dd J = 8.2,

1.0Hz) 7.51(1H, s) 7.53(1H, s) 7.91(1H, s)1.0 Hz) 7.51 (1H, s) 7.53 (1H, s) 7.91 (1H, s)

9.44(1H,s)9.44 (1H, s)

실시예 3. 에틸 2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복실레이트Example 3. Ethyl 2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxylate

참고예 2의 화합물 3-메틸-1H-6-인돌카바알데하이드 0.50 g(3.1 mmole)을 에탄올 60 ml에 용해한 후 에틸 카바자이드 0.49 g(4.6 mmole)과 농염산 촉매량을 반응용액에 투입하고 14시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 액상을 디클로로메탄 100 ml에 용해시키고 유기층을 증류수 100 ml(2회)로 세척했다. 분리한 유기층을 감압증류하여 얻은 고상물을 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올 = 95:5 )법을 이용하여 백색의 표제 고상물 0.46 g(59.7%)을 수득하였다.0.50 g (3.1 mmole) of the compound 3-methyl- 1H -6-indolecarbaaldehyde of Reference Example 2 was dissolved in 60 ml of ethanol, and 0.49 g (4.6 mmole) of ethyl carbazide and a catalytic amount of concentrated hydrochloric acid were added to the reaction solution for 14 hours. Reflux for a while. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then dissolved in 100 ml of dichloromethane. The organic layer was washed with 100 ml of distilled water (twice). 0.46 g (59.7%) of white title solids were obtained by column chromatography (silica gel, dichloromethane: methanol = 95: 5).

M.P : 169 ∼ 171 ℃M.P: 169-171 ° C

1H NMR(DMSO-d6): 1.24(3H, t J=7.1Hz) 2.25(3H, d J=1.0Hz) 4.15(2H, q, 1 H NMR (DMSO-d 6 ): 1.24 (3H, t J = 7.1 Hz) 2.25 (3H, d J = 1.0 Hz) 4.15 (2H, q,

J=7.1Hz) 7.20(1H, dd, J=2.2, 1.0 Hz) 7.31(1H, dd,J = 7.1 Hz) 7.20 (1H, dd, J = 2.2, 1.0 Hz) 7.31 (1H, dd,

J=8.3, 1.3Hz) 7.49(1H, d J=8.3Hz) 7.55(1H, s)J = 8.3, 1.3 Hz) 7.49 (1H, d J = 8.3 Hz) 7.55 (1H, s)

8.07(1H, s) 10.89(1H, s)8.07 (1H, s) 10.89 (1H, s)

실시예 4. 2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복실산Example 4 2N- (3-Methyl- 1H -6-indolylmethylene) hydrazinecarboxylic acid

실시예 3의 에스테르화합물 0.25 g(1.0 mmole)을 메탄올 20ml에 용해한 후 리튬하이드로옥사이드 0.25 g을 투입하고 1시간 30분간 환류 교반시켰다. 반응용액을 감압증류하여 얻은 액상을 증류수 20 ml에 용해시킨 후 0.1N 염산용액으로 pH 4.5까지 조절하여 석출된 물질을 여과 건조하여 연갈색의 표제화합물 0.18 g (81.3%)을 수득하였다.0.25 g (1.0 mmole) of the ester compound of Example 3 was dissolved in 20 ml of methanol, and 0.25 g of lithium hydroxide was added thereto, and the mixture was stirred under reflux for 1 hour and 30 minutes. The liquid obtained by distillation of the reaction solution under reduced pressure was dissolved in 20 ml of distilled water, and then adjusted to pH 4.5 with 0.1 N hydrochloric acid solution. The precipitated material was filtered and dried to yield 0.18 g (81.3%) of the title compound as light brown.

M.P : 220 ℃ 분해M.P: 220 ℃ decomposition

1H NMR(CDCl3): 2.28(3H, d, J=1.0Hz) 7.26(1H, dd, J=2.2, 1.0 Hz) 1 H NMR (CDCl 3 ): 2.28 (3H, d, J = 1.0 Hz) 7.26 (1H, dd, J = 2.2, 1.0 Hz)

7.32(1H, dd, J=8.3, 1.3Hz) 7.45(1H, d, J=8.3Hz)7.32 (1H, dd, J = 8.3, 1.3 Hz) 7.45 (1H, d, J = 8.3 Hz)

7.58(1H, s) 8.07(1H, s) 10.89(1H, s) 11.55(1H, brs)7.58 (1 H, s) 8.07 (1 H, s) 10.89 (1 H, s) 11.55 (1 H, brs)

실시예 5. 2N-(3-메틸-1H-6-인돌)카바알데하이드 2-피리디노히드라존Example 5 2N- (3-methyl- 1H -6-indole) carbaldehyde 2-pyridinohydrazone

참고예 2의 화합물 3-메틸-1H-6-인돌카바알데하이드 0.40 g(2.5 mmole)을 에탄올 50 ml에 용해한 후 2-히드라지노피리딘 0.37 g(3.3 mmole)과 농염산 촉매량을 반응용액에 투입하고 10시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 액상을 디클로로메탄 100 ml에 용해시키고 유기층을 증류수 100 ml(2회)로 세척했다. 분리한 유기층을 감압증류하여 얻은 고상물을 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올 = 95:5 )법을 이용하여 백색의 표제 고상물 0.52 g(82.7%)을 수득하였다.0.40 g (2.5 mmole) of the compound 3-methyl- 1H -6-indolecarbaaldehyde of Reference Example 2 was dissolved in 50 ml of ethanol, and 0.37 g (3.3 mmole) of 2-hydrazinopyridine and a catalytic amount of concentrated hydrochloric acid were added to the reaction solution. It was refluxed for 10 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then dissolved in 100 ml of dichloromethane. The organic layer was washed with 100 ml of distilled water (twice). The separated organic layer was distilled under reduced pressure to give 0.52 g (82.7%) of a white title solid by column chromatography (silica gel, dichloromethane: methanol = 95: 5).

M.P : 220 ∼ 221 ℃M.P: 220 ~ 221 ℃

1H NMR(DMSO-d6): 2.25(3H, d, J=0.9Hz) 6.66(1H, tdd, J=4.9, 0.9Hz)1 H NMR (DMSO-d 6 ): 2.25 (3H, d, J = 0.9 Hz) 6.66 (1H, tdd, J = 4.9, 0.9 Hz)

7.17(1H, dd, J=2.1, 1.0Hz) 7.22(1H, d, J=8.4Hz)7.17 (1H, dd, J = 2.1, 1.0 Hz) 7.22 (1H, d, J = 8.4 Hz)

7.39(1H, dd, J=8.3, 1.3Hz) 7.49(1H, d, J=8.2Hz)7.39 (1H, dd, J = 8.3, 1.3 Hz) 7.49 (1H, d, J = 8.2 Hz)

7.54(1H, s) 7.64(1H, m) 8.08(2H, m) 10.61(1H, s)7.54 (1H, s) 7.64 (1H, m) 8.08 (2H, m) 10.61 (1H, s)

10.77(1H, s)10.77 (1H, s)

실시예 6. (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)히드라진카르보티오아미드Example 6. (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) hydrazinecarbothioamide

참고예 3의 화합물 0.30 g(1.32 mmmole)과 티오세미카바자이드 0.24 g(2.64 mmmole)을 출발물질로 하여 실시예 2와 같이 반응을 진행하여 연갈색 고상물의 표제화합물 0.34 g(85.7%)을 수득하였다.The reaction was conducted in the same manner as in Example 2, using 0.30 g (1.32 mmmole) of the compound of Reference Example 3 and 0.24 g (2.64 mmmole) of thiosemicarbazide as starting materials to obtain 0.34 g (85.7%) of the title compound as a light brown solid. .

M.P : 115 ∼ 117 ℃M.P: 115-117 ℃

1H NMR(CDCl3): 1.79(2H, m) 1.90(4H, m) 2.22(2H, m) 2.32(3H, d, 1 H NMR (CDCl 3 ): 1.79 (2H, m) 1.90 (4H, m) 2.22 (2H, m) 2.32 (3H, d,

J=1.0Hz) 4.79(1H, m) 6.34(1H, brs) 7.15(1H, d,J = 1.0 Hz) 4.79 (1 H, m) 6.34 (1 H, brs) 7.15 (1 H, d,

J=1.0,Hz) 7.27(1H, brs) 7.44(1H, dd, J=8.3, 1.4Hz)J = 1.0, Hz) 7.27 (1H, brs) 7.44 (1H, doublet of doublets, J = 8.3, 1.4 Hz)

7.54(1H, s) 7.57(1H, d, J=0.6Hz) 7.96(1H, d, J=1.0Hz)7.54 (1H, s) 7.57 (1H, d, J = 0.6 Hz) 7.96 (1H, d, J = 1.0 Hz)

9.44(1H, s)9.44 (1 H, s)

실시예 7. (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴에틸렌)히드라진카르복사아미드Example 7. (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylethylene) hydrazinecarboxamide

참고예 5의 화합물 1-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴)-1-에탄온 0.15 g(0.62 mmole)을 에탄올 50 ml에 용해한 후 티오세미카바자이드 0.17 g(1.55 mmole)과 농염산 촉매량을 반응용액에 투입하고 20시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 고상을 이소프로필알콜로 재결정하여 연백색의 표제 고상물 0.13 g(70.1%)을 수득하였다.0.17 g (0.62 mmole) of Compound 1- (3-methyl-1N-cyclopentyl- 1H -6-indolyl) -1-ethanone of Reference Example 5 was dissolved in 50 ml of ethanol, and then 0.17 g (1.55) of thiosemicarbazide mmole) and concentrated hydrochloric acid were added to the reaction solution and refluxed for 20 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to recrystallize with isopropyl alcohol to give 0.13 g (70.1%) of a pale white title solid.

M.P :182 ∼ 183 ℃M.P: 182-183 ℃

1H NMR(CDCl3): 1.73(2H, m) 1.91(4H, m) 2.20(2H, m) 2.32(3H, d, 1 H NMR (CDCl 3 ): 1.73 (2H, m) 1.91 (4H, m) 2.20 (2H, m) 2.32 (3H, d,

J=0.5Hz) 2.65(3H, s) 4.77(1H, m) 7.01(1H, s)J = 0.5 Hz) 2.65 (3H, s) 4.77 (1H, m) 7.01 (1H, s)

7.47(1H, dd, J=8.2, 1.0Hz) 7.46(1H, s) 7.56(1H, s)7.47 (1H, dd, J = 8.2, 1.0 Hz) 7.46 (1H, s) 7.56 (1H, s)

7.95(1H, s)7.95 (1 H, s)

실시예 8. (E)-2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복스이미다미드Example 8. (E) -2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboximidamide

참고예 2의 화합물 3-메틸-1H-6-인돌카바알데하이드 0.40 g(2.51 mmole)과 아미노구아니딘 염산염 0.27 g(2.51 mmmole)을 출발물질로 하여 실시예 1과 같이 반응을 진행시켜 백색 고상물의 표제화합물 0.35 g(64.7%)을 수득하였다.The title compound of the white solid product was subjected to the reaction as in Example 1, using 0.40 g (2.51 mmole) of the compound 3-methyl- 1H -6-indolecarbaaldehyde and 0.27 g (2.51 mmmole) of the aminoguanidine hydrochloride as reference materials. 0.35 g (64.7%) was obtained.

M.P : 193 ∼ 195℃M.P: 193-195 ℃

1H NMR(DMSO-d6): 2.26(3H, d, J=0.8Hz) 7.23(1H, d, J=1.8Hz) 7.51(1H, 1 H NMR (DMSO-d 6 ): 2.26 (3H, d, J = 0.8 Hz) 7.23 (1H, d, J = 1.8 Hz) 7.51 (1H,

d, J=8.3Hz) 7.59(1H, dd, J=8.3, 1.3Hz) 7.68(1H, s)d, J = 8.3 Hz) 7.59 (1H, dd, J = 8.3, 1.3 Hz) 7.68 (1H, s)

8.22(1H, s) 10.85(1H, s)8.22 (1H, s) 10.85 (1H, s)

실시예 9. (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)카르보히드라자이드Example 9. (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) carbohydrazide

참고예 3의 화합물 3-메틸-1N-싸이클로펜틸-1H-6-인돌카바알데하이드 0.30 g(1.32 mmole) 및 카르보히드라진 0.36 g(2.9 mmole)을 에탄올 80 ml와 물 20 ml에 현탁시킨 후 초산 0.5 ml을 투입하여 용해시킨 다음 40 ℃에서 10시간 동안 교반했다. 형성된 침전물을 여과하고 얻은 용액을 증류하여 에탄올을 제거한 후 메틸렌클로라이드로 추출하고 유기용액층을 0.1N 염산용액으로 세척, 건조하여 미색 유상물을 수득하였다. 수득된 유상물을 아세토니트릴에 교반하면서 용해시켜 백색 고상물 표제화합물 0.32 g(80.9%)을 수득하였다.0.30 g (1.32 mmole) of 3-methyl-1N-cyclopentyl- 1H -6-indolecarbaaldehyde and 0.36 g (2.9 mmole) of carbohydrazine in Reference Example 3 were suspended in 80 ml of ethanol and 20 ml of water, followed by acetic acid. 0.5 ml was added and dissolved, followed by stirring at 40 ° C. for 10 hours. The precipitate formed was filtered and the obtained solution was distilled to remove ethanol, extracted with methylene chloride, and the organic solution layer was washed with 0.1 N hydrochloric acid solution and dried to obtain an off-white oil. The resulting oil was dissolved in acetonitrile while stirring to give 0.32 g (80.9%) of a white solid title compound.

M.P : 219 ∼ 221℃M.P: 219∼221 ° C

1H NMR(DMSO-d6): 1.76(2H, m) 1.88(4H, m) 2.18(2H, m) 2.89(3H, s) 1 H NMR (DMSO-d 6 ): 1.76 (2H, m) 1.88 (4H, m) 2.18 (2H, m) 2.89 (3H, s)

4.94(1H, m) 7.34(1H, d, J=0.7Hz) 7.52(2H, m)4.94 (1H, m) 7.34 (1H, d, J = 0.7 Hz) 7.52 (2H, m)

7.77(1H, s) 8.30(1H, brs) 10.56(1H, s)7.77 (1H, s) 8.30 (1H, brs) 10.56 (1H, s)

실시예 10. (E)-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)-2N-아세틱히드라존Example 10. (E)-(3-Methyl-1N-cyclopentyl- 1H -6-indolylmethylene) -2N-acetichydrazone

참고예 3의 화합물 3-메틸-1N-싸이클로펜틸-1H-6-인돌카바알데하이드 0.30 g(1.3 mmole)을 에탄올 50 ml에 용해한 후 아세틱히드라자이드 0.20 g(2.6 mmole)과 농염산 촉매량을 반응용액에 투입하고 14시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 액상을 디클로로메탄 100 ml에 용해시키고 유기층을 증류수 100 ml(2회)로 세척했다. 분리한 유기층을 감압증류하여 얻은 고상물을 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올 = 95:5 )법을 이용하여 백색의 표제 고상물 0.32 g(85.6%)을 수득하였다.0.30 g (1.3 mmole) of the compound 3-methyl-1N-cyclopentyl- 1H -6-indolecarbaaldehyde of Reference Example 3 was dissolved in 50 ml of ethanol, and then 0.20 g (2.6 mmole) of acetichydrazide and the amount of concentrated hydrochloric acid were reacted. It was added to the solution and refluxed for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then dissolved in 100 ml of dichloromethane. The organic layer was washed with 100 ml of distilled water (twice). The solid obtained by distillation under reduced pressure of the separated organic layer was subjected to column chromatography (silica gel, dichloromethane: methanol = 95: 5) to obtain 0.32 g (85.6%) of the white title solid.

M.P :86 ∼ 88 ℃M.P: 86-88 ℃

1H NMR(DMSO-d6): 1.83(2H, m) 1.94(4H, m) 2.24(2H, m) 2.36(3H, d, 1 H NMR (DMSO-d 6 ): 1.83 (2H, m) 1.94 (4H, m) 2.24 (2H, m) 2.36 (3H, d,

J=0.9Hz) 2.46(3H, s) 2.84(1H, m) 7.08(1H, d,J = 0.9 Hz) 2.46 (3H, s) 2.84 (1H, m) 7.08 (1H, d,

J=1.0Hz) 7.50(1H, dd, J=8.3, 1.3Hz) 7.58(1H, d,J = 1.0 Hz) 7.50 (1H, dd, J = 8.3, 1.3 Hz) 7.58 (1H, d,

J=8.3Hz) 7.61(1H, s) 7.90(1H, s) 9.07(1H, s)J = 8.3 Hz) 7.61 (1H, s) 7.90 (1H, s) 9.07 (1H, s)

실시예 11. (E)-2N-(3-메틸-1N-벤질-1H-6-인돌릴메틸렌)히드라진카르복사아미드Example 11. (E) -2N- (3-methyl-1N-benzyl- 1H -6-indolylmethylene) hydrazinecarboxamide

참고예 6의 화합물 3-메틸-1N-벤질-1H-6-인돌카바알데하이드 0.30 g(1.3 mmole)을 에탄올 50 ml에 용해시킨 후 세미카바자이드 염산염 0.30 g(2.6 mmole)과 농염산 촉매량을 반응용액에 투입하고 14시간 동안 환류시켰다. 반응용액을 실온으로 냉각시킨 후 감압농축하여 얻은 액상을 디클로로메탄 100 ml에 용해시키고 유기층을 증류수 100 ml(2회)로 세척했다. 분리한 유기층을 감압증류하여 얻은 고상물을 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올 = 95:5 )법을 이용하여 백색의 표제 고상물 0.32 g(87.1%)을 수득하였다.0.30 g (1.3 mmole) of Compound 3-methyl-1N-benzyl- 1H -6-indolecarbaaldehyde of Reference Example 6 was dissolved in 50 ml of ethanol, followed by reacting 0.30 g (2.6 mmole) of semicarbazide hydrochloride with a catalytic amount of concentrated hydrochloric acid. It was added to the solution and refluxed for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then dissolved in 100 ml of dichloromethane. The organic layer was washed with 100 ml of distilled water (twice). 0.32 g (87.1%) of a white title solid was obtained by column chromatography (silica gel, dichloromethane: methanol = 95: 5).

M.P :125 ∼ 127 ℃M.P: 125-127 ℃

1H NMR(CDCl3): 2.32(3H, s) 5.27(2H,s) 6.95(1H, d, J=1.1Hz) 1 H NMR (CDCl 3 ): 2.32 (3H, s) 5.27 (2H, s) 6.95 (1H, d, J = 1.1 Hz)

7.10(2H, d, J=6.4Hz) 7.29(3H, m) 7.41(1H, s)7.10 (2H, d, J = 6.4 Hz) 7.29 (3H, m) 7.41 (1H, s)

7.44(1H, dd, J=8.3, 1.3 Hz) 7.56(1H, d. J=8.3 Hz)7.44 (1H, doublet of doublets, J = 8.3, 1.3 Hz) 7.56 (1H, d. J = 8.3 Hz)

7.77 (1H,s)7.77 (1 H, s)

실험예Experimental Example

본 발명의 화합물 또는 그 약학적 허용 염이 포스포디에스터라제 IV 또는 종양괴사인자를 저해하고, 따라서 천식, 관절염, 골관절염, 기관지염, 만성 기도 폐쇄 질병, 건선, 알레르기성 비염, 피부염, AIDS, HIV, 크론씨(Crohn's) 질병, 패혈증, 패혈병에 의한 충격(shock), 악태증, 기타 염증 질병 또는 종양괴사인자(TNF)의 생산을 포함하는 질병들을 치료한다는 효과는 하기 실험에 의해 나타냈다.Compounds of the present invention or pharmaceutically acceptable salts thereof inhibit phosphodiesterase IV or tumor necrosis factor, thus asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV The effect of treating diseases including Crohn's disease, sepsis, septic shock, malaria, other inflammatory diseases or the production of tumor necrosis factor (TNF) was shown by the following experiment.

[실험방법]Experimental Method

사람 U 937 세포로부터 부분 정제한 PDE IV와 테스트 화합물, 그리고 0.01 μM [3H] cAMP가 들어있는 1.0 μM cAMP를 30℃에서 20분동안 인큐베이션했다. 그후 상기 혼합물을 2분동안 끓여서 cAMP가 AMP로 변화되는 포스포디에스터라제 반응을 완결했다. 여기에 스네이크(snake) 베놈(venom) 누클레오티다아제(nucleotidase)를 첨가하고 30℃에서 10분동안 인큐베이션하여 AMP를 아데노신(adenosine)으로 변화시켰다. 가수분해되지 않은(Unhydrolyzed) cAMP는 AG1-X2 수지(resin)와 결합되고, 수용액 상태의 남아있는 [3H] 아데노신을 신틸레이션(scintillation) 카운팅에 의해 정량했다. 비교군으로서 화합물명이 4-[3-(사이클로펜틸옥시)-4-메톡시페닐]피롤리딘-2-온인 롤리프람(Rolipram)을 사용했다. 롤리프람의 약리기전은 cAMP-특이적인 포스포디에스테라제의 선별적이고 기본적인(prototypical) 저해제이다.Partially purified PDE IV from human U 937 cells, 1.0 μM cAMP containing test compound and 0.01 μM [ 3 H] cAMP were incubated at 30 ° C. for 20 minutes. The mixture was then boiled for 2 minutes to complete the phosphodiesterase reaction in which cAMP was changed to AMP. Snamp venom nucleotidase was added thereto and incubated at 30 ° C. for 10 minutes to change AMP to adenosine. Unhydrolyzed cAMP was bound to AG1-X2 resin and the remaining [ 3 H] adenosine in aqueous solution was quantified by scintillation counting. As a comparative group, Rolipram having a compound name of 4- [3- (cyclopentyloxy) -4-methoxyphenyl] pyrrolidin-2-one was used. The pharmacological mechanism of rolipram is a selective and prototypical inhibitor of cAMP-specific phosphodiesterases.

[약리 결과][Pharmacological Results]

결과는 하기 표 1에 나타냈다.The results are shown in Table 1 below.

억제 %를 계산하는 식은 다음과 같다:The formula for calculating the% inhibition is as follows:

억제 % = [(대조군-블랭크)-(샘플-블랭크)]/(대조군-블랭크) X 100Inhibition% = [(Control-Blank)-(Sample-Blank)] / (Control-Blank) X 100

여기서, 대조군 : 효소를 넣고 시료를 넣지 않았을 때 카운트한 값Here, the control: counted when the enzyme is added and the sample is not added

블랭크 : 효소와 시료를 넣지 않았을 때 카운트한 값Blank: Counted value without enzyme and sample

샘플 : 효소와 시료를 넣었을 때 카운트한 값Sample: Value counted with enzyme and sample

표 1Table 1

포스포디에스터라제 IV 에 대한 억제%% Inhibition against phosphodiesterase IV

화합물compound 농도 (μM)Concentration (μM) 억제%control% 롤리프람(비교물질)Rolipram (Comparative) 1.00.31.00.3 64.353.064.353.0 실시예 1Example 1 1.00.31.00.3 36.326.536.326.5 실시예 2Example 2 1.00.31.00.3 52.946.552.946.5 실시예 3Example 3 1.00.31.00.3 28.918.528.918.5 실시예 4Example 4 1.00.31.00.3 41.532.641.532.6 실시예 5Example 5 1.00.31.00.3 32.320.332.320.3 실시예 6Example 6 1.00.31.00.3 55.746.655.746.6 실시예 7Example 7 1.00.31.00.3 58.941.658.941.6 실시예 8Example 8 1.00.31.00.3 35.932.535.932.5 실시예 9Example 9 1.00.31.00.3 29.618.929.618.9 실시예 10Example 10 1.00.31.00.3 46.938.646.938.6 실시예 11Example 11 1.00.31.00.3 68.754.668.754.6

본 발명의 상기 화학식 1의 화합물 또는 그 약학적 허용 염은 포스포디에스터라제 IV 또는 종양괴사인자에 대한 억제효과를 지니며, 따라서, 천식, 관절염, 골관절염, 기관지염, 만성 기도 폐쇄 질병, 건선, 알레르기성 비염, 피부염, AIDS, HIV, 크론씨(Crohn's) 질병, 패혈증, 패혈병에 의한 충격(shock), 악태증, 기타 염증 질병들 또는 종양괴사인자(TNF)의 생산을 포함하는 질병들에 대한 치료에 유용하다.The compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention has an inhibitory effect on phosphodiesterase IV or tumor necrosis factor, and thus, asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, For diseases including allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock, etiology, other inflammatory diseases or the production of tumor necrosis factor (TNF) It is useful for treatment.

비록 상기에서 본 발명은 기재된 구체예를 중심으로 상세히 설명되었지만, 본 발명의 범주 및 기술사상 범위 내에서 다양한 변형 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Although the invention has been described in detail above with reference to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope and spirit of the invention, and such variations and modifications are within the scope of the appended claims. It is natural to belong.

Claims (16)

하기 화학식 1의 화합물 또는 그 약학적 허용 염:A compound of Formula 1 or a pharmaceutically acceptable salt thereof: 화학식 1Formula 1 상기 식에서,Where R1는 수소, (C1-C7)알킬, (C3-C7)사이클로알킬, 페닐 또는 벤질이고,R 1 is hydrogen, (C 1 -C 7 ) alkyl, (C 3 -C 7 ) cycloalkyl, phenyl or benzyl, R2는 선택적으로R 2 is optionally i) -C(=O)H,i) -C (= O) H, ii) -C(=X)NH-R4,ii) -C (= X) NH-R 4 , ⅲ) -C(=O)OR5, 또는Iii) -C (= O) OR 5 , or ⅳ) 피리딘기이며,Iii) a pyridine group, X는 O, S 또는 N-R6이고,X is O, S or NR 6 , R3는 수소, (C1-C7)알킬 또는 아릴기이며,R 3 is hydrogen, (C 1 -C 7 ) alkyl or an aryl group, R4는 수소 또는 아민기이고,R 4 is hydrogen or an amine group, R5는 수소 또는 (C1-C3)알킬이며,R 5 is hydrogen or (C 1 -C 3 ) alkyl, R6는 수소 또는 니트릴기이다.R 6 is hydrogen or a nitrile group. 제1항에 있어서,The method of claim 1, 광학이성질체 형태, 또는 광학이성질체들의 혼합물 형태로 존재하는,Present in the form of an optical isomer or a mixture of optical isomers, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.Compound of Formula 1 or a pharmaceutically acceptable salt thereof. 제1항에 있어서,The method of claim 1, 기하이성질체 형태, 또는 기하이성질체들의 혼합물 형태로 존재하는,Present in the form of a geometric isomer or a mixture of geometric isomers, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.Compound of Formula 1 or a pharmaceutically acceptable salt thereof. 제1항에 있어서,The method of claim 1, 상기 화학식 1의 화합물이 (E)-형태인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.The compound of formula 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (1) is in the (E)-form. 제1항에 있어서,The method of claim 1, R1는 싸이클로펜틸 또는 벤질이고,R 1 is cyclopentyl or benzyl, R2는 선택적으로R 2 is optionally i) -C(=O)H,i) -C (= O) H, ii) -C(=X)NH-R4,ii) -C (= X) NH-R 4 , ⅲ) -C(=O)OR5, 또는Iii) -C (= O) OR 5 , or ⅳ) 피리딘기이며,Iii) a pyridine group, X는 O, S 또는 N-R6이고,X is O, S or NR 6 , R3는 수소 또는 메틸기이며,R 3 is hydrogen or a methyl group, R4는 수소 또는 아민기이고,R 4 is hydrogen or an amine group, R5는 수소 또는 에틸기이며,R 5 is hydrogen or an ethyl group, R6는 수소인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.R 6 is hydrogen, the compound of Formula 1 or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복스아미드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of Formula 1 is (E) -2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxamide, the compound of formula (1) or a pharmaceutical thereof Acceptable salts. 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)히드라진카르복스아미드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of Formula 1 is (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) hydrazinecarboxamide, Compound or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화학식 1의 화합물이 에틸 2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복실레이트인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.The compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula 1 is ethyl 2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxylate. 제1항에 있어서, 상기 화학식 1의 화합물이 2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복실산인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.The compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula 1 is 2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboxylic acid. 제1항에 있어서, 상기 화학식 1의 화합물이 2N-(3-메틸-1H-6-인돌)카바알데하이드 2-피리디노히드라존인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.The compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula 1 is 2N- (3-methyl- 1H -6-indole) carbaaldehyde 2-pyridinohydrazone . 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)히드라진카르보티오아미드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of formula 1 is (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) hydrazinecarbothioamide, characterized in that Of a compound or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴에틸렌)히드라진카르복사아미드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of Formula 1 is (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylethylene) hydrazinecarboxamide, Compound or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-2N-(3-메틸-1H-6-인돌릴메틸렌)히드라진카르복스이미다미드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of formula 1 is (E) -2N- (3-methyl- 1H -6-indolylmethylene) hydrazinecarboximidamide, the compound of formula 1 or Pharmaceutically acceptable salts. 제1항에 있어서, 상기 화학식 1의 화합물이(E)-2N-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)카르보히드라자이드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of Formula 1 is (E) -2N- (3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) carbohydrazide, Compound or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-(3-메틸-1N-싸이클로펜틸-1H-6-인돌릴메틸렌)-2N-아세틱히드라존인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.According to claim 1, wherein the compound of formula 1 is (E)-(3-methyl-1N-cyclopentyl- 1H -6-indolylmethylene) -2N-acetichydrazone, Formula 1 Of a compound or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화학식 1의 화합물이 (E)-2N-(3-메틸-1N-벤질-1H-6-인돌릴메틸렌)히드라진카르복사아미드인 것을 특징으로 하는, 상기 화학식 1의 화합물 또는 그 약학적 허용 염.The compound of formula 1 according to claim 1, wherein the compound of formula 1 is (E) -2N- (3-methyl-1N-benzyl- 1H -6-indolylmethylene) hydrazinecarboxamide Or pharmaceutically acceptable salts thereof.
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